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Differences in gene-wide DNA methylation of the Alzheimer’s disease (AD)-associated genes BIN1, HLA-DRB5, SORL1, SLC24A4, and ABCA7 are reported to be associated with AD in post-mortem brain samples. We investigated whether the same associations could be found in leukocytes collected pre-mortem. Using cohort data of 544 Swedish twins (204 dementia diagnoses), we replicated the findings in HLA-DRB5 and SLC24A4 at P

Abstract Polygenic risk scores (PRSs) can boost risk prediction in late-onset Alzheimer’s disease (LOAD) beyond apolipoprotein E (APOE) but have not been leveraged to identify genetic resilience factors. Here, we sought to identify resilience-conferring common genetic variants in (1) unaffected individuals having high PRSs for LOAD, and (2) unaffected APOE-ε4 carriers also having high PRSs for LOAD. We used genome-wide association study (GWAS) to contrast “resilient” unaffected individuals at the highest genetic risk for LOAD with LOAD cases at comparable risk. From GWAS results, we constructed polygenic resilience scores to aggregate the addictive contributions of risk-orthogonal common variants that promote resilience to LOAD. Replication of resilience scores was undertaken in eight independent studies. We successfully replicated two polygenic resilience scores that reduce genetic risk penetrance for LOAD. We also showed that polygenic resilience scores positively correlate with polygenic risk scores in unaffected individuals, perhaps aiding in staving off disease. Our findings align with the hypothesis that a combination of risk-independent common variants mediates resilience to LOAD by moderating genetic disease risk.

Abstract We tested the causality between education and smoking using the natural experiment of discordant twin pairs allowing to optimally control for background genetic and childhood social factors. Data from 18 cohorts including 10,527 monozygotic (MZ) and same-sex dizygotic (DZ) twin pairs discordant for education and smoking were analyzed by linear fixed effects regression models. Within twin pairs, education levels were lower among the currently smoking than among the never smoking co-twins and this education difference was larger within DZ than MZ pairs. Similarly, education levels were higher among former smoking than among currently smoking co-twins, and this difference was larger within DZ pairs. Our results support the hypothesis of a causal effect of education on both current smoking status and smoking cessation. However, the even greater intra-pair differences within DZ pairs, who share only 50% of their segregating genes, provide evidence that shared genetic factors also contribute to these associations.

Abstract We leveraged a unique school‐based longitudinal cohort—the Project Talent Aging Study—to examine whether attending higher quality schools is associated with cognitive performance among older adults in the United States (mean age = 74.8). Participants (n = 2,289) completed telephone neurocognitive testing. Six indicators of high school quality, reported by principals at the time of schooling, were predictors of respondents’ cognitive function 58 years later. To account for school‐clustering, multilevel linear and logistic models were applied. We found that attending schools with a higher number of teachers with graduate training was the clearest predictor of later‐life cognition, and school quality mattered especially for language abilities. Importantly, Black respondents (n = 239; 10.5 percentage) were disproportionately exposed to low quality high schools. Therefore, increased investment in schools, especially those that serve Black children, could be a powerful strategy to improve later life cognitive health among older adults in the United States.

BackgroundCognitive testing in large population surveys is frequently used to describe cognitive aging and determine the incidence rates, risk factors, and long-term trajectories of the development of cognitive impairment. As these surveys are increasingly administered on internet-based platforms, web-based and self-administered cognitive testing calls for close investigation. ObjectiveWeb-based, self-administered versions of 2 age-sensitive cognitive tests, the Stop and Go Switching Task for executive functioning and the Figure Identification test for perceptual speed, were developed and administered to adult participants in the Understanding America Study. We examined differences in cognitive test scores across internet device types and the extent to which the scores were associated with self-reported distractions in everyday environments in which the participants took the tests. In addition, national norms were provided for the US population. MethodsData were collected from a probability-based internet panel representative of the US adult population—the Understanding America Study. Participants with access to both a keyboard- and mouse-based device and a touch screen–based device were asked to complete the cognitive tests twice in a randomized order across device types, whereas participants with access to only 1 type of device were asked to complete the tests twice on the same device. At the end of each test, the participants answered questions about interruptions and potential distractions that occurred during the test. ResultsOf the 7410 (Stop and Go) and 7216 (Figure Identification) participants who completed the device ownership survey, 6129 (82.71% for Stop and Go) and 6717 (93.08% for Figure Identification) participants completed the first session and correctly responded to at least 70% of the trials. On average, the standardized differences across device types were small, with the absolute value of Cohen d ranging from 0.05 (for the switch score in Stop and Go and the Figure Identification score) to 0.13 (for the nonswitch score in Stop and Go). Poorer cognitive performance was moderately associated with older age (the absolute value of r ranged from 0.32 to 0.61), and this relationship was comparable across device types (the absolute value of Cohen q ranged from 0.01 to 0.17). Approximately 12.72% (779/6123 for Stop and Go) and 12.32% (828/6721 for Figure Identification) of participants were interrupted during the test. Interruptions predicted poorer cognitive performance (P

Abstract Body mass index (BMI) is associated with cognitive abilities, but the nature of the relationship remains largely unexplored. We aimed to investigate the bidirectional relationship from midlife through late-life, while considering sex differences and genetic predisposition to higher BMI. We used data from 23,892 individuals of European ancestry from the Health and Retirement Study, with longitudinal data on BMI and three established cognitive indices: mental status, episodic memory, and their sum, called total cognition. To investigate the dynamic relationship between BMI and cognitive abilities, we applied dual change score models of change from age 50 through 89, with a breakpoint at age 65 or 70. Models were further stratified by sex and genetic predisposition to higher BMI using tertiles of a polygenic score for BMI (PGSBMI). We demonstrated bidirectional effects between BMI and all three cognitive indices, with higher BMI contributing to steeper decline in cognitive abilities in both midlife and late-life, and higher cognitive abilities contributing to less decline in BMI in late-life. The effects of BMI on change in cognitive abilities were more evident in men compared to women, and among those in the lowest tertile of the PGSBMI compared to those in the highest tertile, while the effects of cognition on BMI were similar across groups. In conclusion, these findings highlight a reciprocal relationship between BMI and cognitive abilities, indicating that the negative effects of a higher BMI persist from midlife through late-life, and that weight-loss in late-life may be driven by cognitive decline.

BackgroundLate-life exposure to ambient air pollution is a modifiable risk factor for dementia, but epidemiological studies have shown inconsistent evidence for cognitive decline. Air quality (AQ) improvement has been associated with improved cardiopulmonary health and decreased mortality, but to the best of our knowledge, no studies have examined the association with cognitive function. We examined whether AQ improvement was associated with slower rate of cognitive decline in older women aged 74 to 92 years.Methods and findingsWe studied a cohort of 2,232 women residing in the 48 contiguous US states that were recruited from more than 40 study sites located in 24 states and Washington, DC from the Women's Health Initiative (WHI) Memory Study (WHIMS)-Epidemiology of Cognitive Health Outcomes (WHIMS-ECHO) study. They were predominantly non-Hispanic White women and were dementia free at baseline in 2008 to 2012. Measures of annual (2008 to 2018) cognitive function included the modified Telephone Interview for Cognitive Status (TICSm) and the telephone-based California Verbal Learning Test (CVLT). We used regionalized universal kriging models to estimate annual concentrations (1996 to 2012) of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) at residential locations. Estimates were aggregated to the 3-year average immediately preceding (recent exposure) and 10 years prior to (remote exposure) WHIMS-ECHO enrollment. Individual-level improved AQ was calculated as the reduction from remote to recent exposures. Linear mixed effect models were used to examine the associations between improved AQ and the rates of cognitive declines in TICSm and CVLT trajectories, adjusting for sociodemographic (age; geographic region; race/ethnicity; education; income; and employment), lifestyle (physical activity; smoking; and alcohol), and clinical characteristics (prior hormone use; hormone therapy assignment; depression; cardiovascular disease (CVD); hypercholesterolemia; hypertension; diabetes; and body mass index [BMI]). For both PM2.5 and NO2, AQ improved significantly over the 10 years before WHIMS-ECHO enrollment. During a median of 6.2 (interquartile range [IQR] = 5.0) years of follow-up, declines in both general cognitive status (β = -0.42/year, 95% CI: -0.44, -0.40) and episodic memory (β = -0.59/year, 95% CI: -0.64, -0.54) were observed. Greater AQ improvement was associated with slower decline in TICSm (βPM2.5improvement = 0.026 per year for improved PM2.5 by each IQR = 1.79 μg/m3 reduction, 95% CI: 0.001, 0.05; βNO2improvement = 0.034 per year for improved NO2 by each IQR = 3.92 parts per billion [ppb] reduction, 95% CI: 0.01, 0.06) and CVLT (βPM2.5 improvement = 0.070 per year for improved PM2.5 by each IQR = 1.79 μg/m3 reduction, 95% CI: 0.02, 0.12; βNO2improvement = 0.060 per year for improved NO2 by each IQR = 3.97 ppb reduction, 95% CI: 0.005, 0.12) after adjusting for covariates. The respective associations with TICSm and CVLT were equivalent to the slower decline rate found with 0.9 to 1.2 and1.4 to 1.6 years of younger age and did not significantly differ by age, region, education, Apolipoprotein E (ApoE) e4 genotypes, or cardiovascular risk factors. The main limitations of this study include measurement error in exposure estimates, potential unmeasured confounding, and limited generalizability.ConclusionsIn this study, we found that greater improvement in long-term AQ in late life was associated with slower cognitive declines in older women. This novel observation strengthens the epidemiologic evidence of an association between air pollution and cognitive aging.

Abstract Background While a high body mass index (BMI) in midlife is associated with higher risk of dementia, high BMI in late-life may be associated with lower risk. This study combined genetic designs with longitudinal data to achieve a better understanding of this paradox. Methods We used longitudinal data from 22,156 individuals in the Swedish Twin Registry (STR) and 25,698 from the Health and Retirement Study (HRS). The STR sample had information about BMI from early adulthood through late-life, and the HRS sample from age 50 through late-life. Survival analysis was applied to investigate age-specific associations between BMI and dementia risk. To examine if the associations are influenced by genetic susceptibility to higher BMI, an interaction between BMI and a polygenic score for BMI (PGSBMI) was included in the models and results stratified into those with genetic predisposition to low, medium, and higher BMI. In the STR, co-twin control models were applied to adjust for familial factors beyond those captured by the PGSBMI. Results At age 35–49, 5 units higher BMI was associated with 15% (95% CI 7–24%) higher risk of dementia in the STR. There was a significant interaction (p = 0.04) between BMI and the PGSBMI, and the association present only among those with genetic predisposition to low BMI (HR 1.38, 95% CI 1.08–1.78). Co-twin control analyses indicated genetic influences. After age 80, 5 units higher BMI was associated with 10–11% lower risk of dementia in both samples. There was a significant interaction between late-life BMI and the PGSBMI in the STR (p = 0.01), but not the HRS, with the inverse association present only among those with a high PGSBMI (HR 0.70, 95% CI 0.52–0.94). No genetic influences were evident from co-twin control models of late-life BMI. Conclusions Not only does the association between BMI and dementia differ depending on age at BMI measurement, but also the effect of genetic influences. In STR, the associations were only present among those with a BMI in opposite direction of their genetic predisposition, indicating that the association between BMI and dementia across the life course might be driven by environmental factors and hence likely modifiable.

In post-industrial settings, apolipoprotein E4 (APOE4) is associated with increased cardiovascular and neurological disease risk. However, the majority of human evolutionary history occurred in environments with higher pathogenic diversity and low cardiovascular risk. We hypothesize that in high-pathogen and energy-limited contexts, the APOE4 allele confers benefits by reducing innate inflammation when uninfected, while maintaining higher lipid levels that buffer costs of immune activation during infection. Among Tsimane forager-farmers of Bolivia (N = 1266, 50% female), APOE4 is associated with 30% lower C-reactive protein, and higher total cholesterol and oxidized LDL. Blood lipids were either not associated, or negatively associated with inflammatory biomarkers, except for associations of oxidized LDL and inflammation which were limited to obese adults. Further, APOE4 carriers maintain higher levels of total and LDL cholesterol at low body mass indices (BMIs). These results suggest that the relationship between APOE4 and lipids may be beneficial for pathogen-driven immune responses and unlikely to increase cardiovascular risk in an active subsistence population.

Abstract Introduction To study if declining cognition drives weight loss in preclinical dementia, we examined the longitudinal association between body mass index (BMI) and cognitive abilities in individuals who did or did not later develop dementia. Methods Using data from individuals spanning age 50 to 89, we applied dual change score models separately in individuals who remained cognitively intact (n = 1498) and those who were diagnosed with dementia within 5 years of last assessment (n = 459). Results Among the cognitively intact, there was a bidirectional association: Stable BMI predicted stable cognition and vice versa. Among individuals who were subsequently diagnosed with dementia, the association was unidirectional: Higher BMI predicted declining cognition but cognition did not predict change in BMI. Discussion Although BMI and cognition stabilized each other when cognitive functioning was intact, this buffering effect was missing in the preclinical dementia phase. This finding indicates that weight loss in preclinical dementia is not driven by declining cognition.

Background: Emerging data suggests PM2.5 (particulate matter with aerodynamic diameter

Abstract Introduction Hormones may be one possible mechanism underlying sex differences in dementia incidence. We examined whether presumed differential prenatal hormone milieu is related to dementia risk by comparing dementia rates in same‐ and opposite‐sex dizygotic twin pairs in male and female twins. Methods The sample comprised 43,254 individuals from dizygotic twin pairs aged 60 and older from the Swedish Twin Registry. Survival analyses were conducted separately for females and males. Results Female twins from opposite‐sex pairs had significantly lower dementia risk than female twins from same‐sex pairs, but the differences emerged only after age 70 (hazard ratio = 0.64, P = 0.004). Results were not explained by postnatal risk factors for dementia, and no interaction between twin type and apolipoprotein E (APOE) ε4 was found. Male twins from same‐sex versus opposite‐sex pairs did not differ significantly. Discussion The results suggest that relatively masculine prenatal hormone milieus correlate with lower dementia risk in females.

BACKGROUND:There is evidence for long-lasting effects of birth characteristics on cognitive ability in childhood and adulthood. Further, low cognitive ability throughout the lifetime has been linked to age-related cognitive decline and dementia risk. However, little is known about the effects of birth characteristics on cognitive dysfunction late in life. Here we explore potential associations between birth characteristics (weight, head circumference, length, and gestational age), adjusted and not adjusted for gestational age, and cognitive impairment and dementia late in life. METHODS AND FINDINGS:Data from twins in the Swedish Twin Registry born 1926-1960 were merged with information from the Swedish birth, patient, and cause of death registries, resulting in a sample of 35,191 individuals. A subsample of 4,000 twins aged 65 years and older also participated in a telephone cognitive screening in 1998-2002. Associations of birth characteristics with registry-based dementia diagnoses and on telephone-assessed cognitive impairment were investigated in the full sample and subsample, respectively. The full sample contained 907 (2.6%) individuals with a dementia diagnosis (an incidence rate of 5.9% per 100,000 person-years), 803 (2.4%) individuals born small for gestational age, and 929 (2.8%) individuals born with a small head for gestational age. The subsample contained 569 (14.2%) individuals with cognitive impairment. Low birth weight for gestational age and being born with a small head for gestational age were significant risk factors for cognitive dysfunction late in life, with an up to 2-fold risk increase (p < 0.001) compared to infants with normal growth and head size, even after controlling for familial factors, childhood socioeconomic status, and education in adulthood. In line with this, each additional 100 g birth weight and each additional millimeter head circumference significantly reduced the risk for dementia (hazard ratio 0.98, 95% confidence interval 0.97 to 0.99, p = 0.004) and cognitive impairment (odds ratio 0.99, 95% confidence interval 0.99 to 1.00, p = 0.004), respectively. Within-pair analyses of identical twins, though hampered by small sample size, suggested that the observed associations between birth characteristics and dementia are likely not due to underlying shared genetic or environmental etiology. A limitation of the present study is that registry-based dementia diagnoses likely miss some of the true dementia cases in the population. Further, a more precise measure of cognitive reserve early in life as well as a date of onset for the cognitive impairment measure in the subsample would have been favorable. CONCLUSIONS:In this study, we found that infants of smaller birth size (i.e., low birth weight or small head circumference adjusted and unadjusted for gestational age) have a significantly higher risk of age-related cognitive dysfunction compared to those with normal growth, highlighting the importance of closely monitoring the cognitive development of such infants and evaluating the potential of early life interventions targeted at enhancing cognitive reserve.

BACKGROUND:Smokers tend to weigh less than never smokers, while successful quitting leads to an increase in body weight. Because smokers and non-smokers may differ in genetic and environmental family background, we analysed data from twin pairs in which the co-twins differed by their smoking behaviour to evaluate if the association between smoking and body mass index (BMI) remains after controlling for family background. METHODS AND FINDINGS:The international CODATwins database includes information on smoking and BMI measured between 1960 and 2012 from 156,593 twin individuals 18-69 years of age. Individual-based data (230,378 measurements) and data of smoking discordant twin pairs (altogether 30,014 pairwise measurements, 36% from monozygotic [MZ] pairs) were analysed with linear fixed-effects regression models by 10-year periods. In MZ pairs, the smoking co-twin had, on average, 0.57 kg/m2 lower BMI in men (95% confidence interval (CI): 0.49, 0.70) and 0.65 kg/m2 lower BMI in women (95% CI: 0.52, 0.79) than the never smoking co-twin. Former smokers had 0.70 kg/m2 higher BMI among men (95% CI: 0.63, 0.78) and 0.62 kg/m2 higher BMI among women (95% CI: 0.51, 0.73) than their currently smoking MZ co-twins. Little difference in BMI was observed when comparing former smoking co-twins with their never smoking MZ co-twins (0.13 kg/m2, 95% CI 0.04, 0.23 among men; -0.04 kg/m2, 95% CI -0.16, 0.09 among women). The associations were similar within dizygotic pairs and when analysing twins as individuals. The observed series of cross-sectional associations were independent of sex, age, and measurement decade. CONCLUSIONS:Smoking is associated with lower BMI and smoking cessation with higher BMI. However, the net effect of smoking and subsequent cessation on weight development appears to be minimal, i.e. never more than an average of 0.7 kg/m2.

Verbal memory is typically studied using immediate recall (IR) and delayed recall (DR) scores, although DR is dependent on IR capability. Separating these components may be useful for deciphering the genetic variation in age-related memory abilities. This study was conducted to (a) construct individual trajectories in IR and independent aspects of delayed recall, or residualized-DR (rDR), across older adulthood; and (b) identify genetic markers that contribute to four estimated phenotypes: IR and rDR levels and changes after age 60. A cognitively intact sample (N = 20,650 with 125,164 observations) was drawn from the U.S. Health and Retirement Study, a nationally representative study of adults aged 50 and older. Mixed effects regression models were constructed using repeated measures from data collected every two years (1996-2012) to estimate level at age 60 and change in memory post-60 in IR and rDR. Genome-wide association scans (GWAS) were conducted in the genotypic subsample (N = 7,486) using ~1.2 million single nucleotide polymorphisms (SNPs). One SNP (rs2075650) in TOMM40 associated with rDR level at the genome-wide level (p = 5.0x10-08), an effect that replicated in an independent sample from the English Longitudinal Study on Ageing (N = 6,898 with 41,328 observations). Meta-analysis of rDR level confirmed the association (p = 5.0x10-11) and identified two others in TOMM40 (rs71352238 p = 1.0x10-10; rs157582 p = 7.0x10-09), and one in APOE (rs769449 p = 3.1 x10-12). Meta-analysis of IR change identified associations with three of the same SNPs in TOMM40 (rs157582 p = 8.3x10-10; rs71352238 p = 1.9x10-09) and APOE (rs769449 p = 2.2x10-08). Conditional analyses indicate GWAS signals on rDR level were driven by APOE, whereas signals on IR change were driven by TOMM40. Additionally, we found that TOMM40 had effects independent of APOE e4 on both phenotypes. Findings from this first U.S. population-based GWAS study conducted on both age-related immediate and delayed verbal memory merit continued examination in other samples and additional measures of verbal memory.

Human height variation is determined by genetic and environmental factors, but it remains unclear whether their influences differ across birth-year cohorts. We conducted an individual-based pooled analysis of 40 twin cohorts including 143,390 complete twin pairs born 1886–1994. Although genetic variance showed a generally increasing trend across the birth-year cohorts, heritability estimates (0.69-0.84 in men and 0.53-0.78 in women) did not present any clear pattern of secular changes. Comparing geographic-cultural regions (Europe, North America and Australia, and East Asia), total height variance was greatest in North America and Australia and lowest in East Asia, but no clear pattern in the heritability estimates across the birth-year cohorts emerged. Our findings do not support the hypothesis that heritability of height is lower in populations with low living standards than in affluent populations, nor that heritability of height will increase within a population as living standards improve.

El objetivo de este experimento fue examinar el recuerdo autobiográfico en mayores con sintomatología depresiva en comparación con mayores no depresivos. 95 mayores son síntomas clínicos depresivos y 90 mayores no depresivos fueron inducidos a generar recuerdos específicos como respuesta a series de palabras clave positivas, negativas y neutras a partir del Test de Memoria Autobiográfica (AMT). Evidencia de una mayor sobregeneralización de aquellos que presentaban síntomas depresivos, sólo fue encontrada para palabras clave negativas, mientras que todos los participantes ofrecieron más recuerdos generales que específicos. Los tiempos de latencia fueron mayores para los participantes con síntomas depresivos que para los no depresivos, pero estos resultados no fueron sólo para los recuerdos específicos. Hubo un fuerte sesgo positivo, con mayor número de recuerdos positivos que negativos, a través de las palabras clave. Los tiempos de latencia no difieren en cuanto a las valencias, pero ante las palabras clave negativas había mayor número de no recuerdo que ante las positivas. Los efectos positivos eran mayores para las persona no depresivas que para aquellos que presentaban síntomas depresivos. Los cambios en el funcionamiento de la memoria relacionados con la edad son presentados como explicación para el patrón de resultados obtenido.

Increasing evidence supports that playing a musical instrument may benefit cognitive development and health at young ages. Whether playing an instrument provides protection against dementia has not been established. In a population-based cotwin control study, we examined the association between playing a musical instrument and whether or not the twins developed dementia or cognitive impairment. Participation in playing an instrument was taken from informant-based reports of twins’ leisure activities. Dementia diagnoses were based on a complete clinical workup using standard diagnostic criteria. Among 157 twin pairs discordant for dementia and cognitive impairment, 27 pairs were discordant for playing an instrument. Controlling for sex, education, and physical activity, playing a musical instrument was significantly associated with less likelihood of dementia and cognitive impairment (odds ratio [OR] = 0.36 [95% confidence interval 0.13–0.99]). These findings support further consideration of music as a modifiable protective factor against dementia and cognitive impairment.

BACKGROUND: The etiology of Parkinson's disease (PD) remains unclear, and environmental risk-factors such as occupation have attracted interest. OBJECTIVE: The goal was to investigate occupational complexity in relation to PD. METHODS: We conducted a population-based cohort study based on the Swedish Twin Registry that included 28,778 twins born between 1886 and 1950. We identified 433 PD cases during the study period. Data on occupation were collected from either the 1970 or 1980 Swedish census, and occupational complexity was assessed via a job exposure matrix. Cox proportional hazard regression analyses with age as the underlying time scale were used to assess PD risk as a function of the three domains of occupational complexity: data, people, and things. Sex and smoking were included as covariates. Analyses stratified by twin pair were conducted to test for confounding by familial factors. RESULTS: High occupational complexity with data and people was associated with increased risk overall (Hazard Ratio [HR] = 1.07, 95% confidence interval [CI] 1.02-1.14, and HR = 1.10, 95% CI 1.01-1.21, respectively), and in men (HR = 1.08, 95% CI 1.01-1.16, and HR = 1.15, 95% CI 1.03-1.28, respectively). Complexity with things was not associated with risk of PD. When the analyses were stratified by twin pair, the HRs for occupational complexity with data and people were attenuated in men. CONCLUSIONS: High complexity of work with data and people is related to increased risk of PD, particularly in men. The attenuation of risk observed in the twin pair-stratified analyses suggests that the association may partly be explained by familial factors, such as inherited traits contributing to occupational selection or other factors shared by twins.

This study examined whether there were neuroanatomical differences evident on CT scans of individuals with dementia who differed on depression history. Neuroanatomical variables consisted of visual ratings of frontal lobe deep white matter, subcortical white matter, and subcortical gray matter hypodensities in the CT scans of 182 individuals from the Study of Dementia in Swedish Twins who were diagnosed with dementia and had information on depression history. Compared to individuals with Alzheimer's disease and no depression, individuals with Alzheimer's disease and late-onset depression (first depressive episode at age 60 or over) had a greater number of striatal hypodensities (gray matter hypodensities in the caudate nucleus and lentiform nucleus). There were no significant differences in frontal lobe deep white matter or subcortical white matter. These findings suggest that late-onset depression may be a process that is distinct from the neurodegenerative changes caused by Alzheimer's disease.

Background. Prior studies report high levels of co-morbidity between major depression (MD) and generalized anxiety disorder (GAD) and suggest that these disorders are closely related genetically. The personality trait of neuroticism (N) is substantially correlated with risk for MD and GAD.Method. Bivariate twin models were applied to lifetime diagnoses of modified DSM-IV diagnosis of MD and GAD obtained at personal interview in 1998–2003 with 37296 twins from the population-based Swedish Twin Registry. A trivariate Cholesky model with N, MD and GAD was applied to a subset (23280 members of same-sex twin pairs) who completed a self-report questionnaire assessing N in 1972–1973.Results. In the best-fit bivariate model, the genetic correlation between MD and GAD was estimated at +1·00 in females and +0·74 in males. Individual-specific environmental factors were also shared between the two disorders with an estimated correlation of +0·59 in males and +0·36 in females. In the best-fit trivariate Cholesky model, genetic factors indexed by N impacted equally on risk for MD and GAD in males and females. However, in both sexes, genetic risk factors indexed by N contributed only around 25% to the genetic correlation between MD and GAD.Conclusion. Genetic risk factors for lifetime MD and GAD are strongly correlated, with higher correlations in women than in men. Although genetic risk factors indexed by the personality trait of N contribute substantially to risk for both MD and GAD, the majority of genetic covariance between the two disorders results from factors not shared with N. [ABSTRACT FROM AUTHOR]

Research findings suggest that dementia risk is lower in individuals with more extensive education, greater engagement in mentally stimulating leisure activities during adulthood, and higher occupational complexity. Other recent findings support the importance of early-life risk factors, such as socioeconomic conditions, early-life development, and exposure to infection, in explaining individual differences in dementia risk. Life-style variables have been conceptualized as delaying factors, postponing onset of dementia and thereby reducing total population burden of dementia. Using a sample of Swedish twins from the HARMONY study, we found that education significantly affects dementia onset, that is, occurrence and timing of dementia symptoms. In the HARMONY data, we also showed that differences in education are reflected in differences in leisure activities and occupation, suggesting that differences in cognitive engagement begin early and persist over the life course. Such findings point to the importance of taking a life-course perspective to designing interventions to delay or to prevent dementia. [ABSTRACT FROM AUTHOR]

Background. In many biomedical disorders, early age at onset (AAO) is an index of high liability to illness which is manifest by an increased risk of illness in relatives. Most but not all prior studies report such a pattern for major depression (MD).Method. Lifetime MD and AAO were assessed at personal interview using modified DSM-III-R criteria in 13864 twin pairs, including 4229 onsets of MD, from the Swedish National Twin Registry. Analyses were conducted using Cox proportional hazards models.Results. Controlling for year of birth, gender, zygosity, co-twin history of MD and the interaction of zygosity and co-twin history, the best-fit model showed a significant main effect and a quadratic effect of AAO of MD in the co-twin on the log hazard ratio for MD in the index twin. When examined together, these effects predicted that from the ages of 15 to ~35 years, AAO of MD is moderately negatively related to risk of illness in relatives. However, past age 35, the function flattens out, with little change of risk in relatives with further increases of AAO. Even when the co-twin had a late AAO, the risk in the index twin substantially exceeded that seen when the co-twin had no history of MD.Conclusion. In this large sample, AAO is a meaningful, albeit modest, index of familial liability to MD. The relationship is nonlinear and results largely from an increased liability in individuals with an early AAO. These results should be interpreted in the context of the limitations of long-term recall. [ABSTRACT FROM AUTHOR]

Linkage studies have identified a large (>60-Mb) region on chromosome 10q that segregates with Alzheimer Disease (AD). Within the region, the gene for insulin degrading enzyme (IDE) represents a notable biological candidate given that it degrades amyloid β-protein (one of the major constituents of senile plaques) and the intracellular amyloid precursor protein (APP) domain released by γ-secretase processing. We have used a single nucleotide polymorphism (SNP) genetic association strategy to investigate AD in relation to a 480-kb region encompassing IDE. A 276-kb linkage disequilibrium block was revealed that spans three genes (IDE, KNSL1, and HHEX). Assessing this block in several independent sets of case-control materials (early- and late-onset AD) and focusing also upon quantitative measures that are pertinent to AD diagnosis and severity (MMSE scores, microtubule-associated protein Tau [MAPT] levels in CSF, degree of brain pathology, and age-at-onset) produced extensive evidence for significant AD association. Signals (p-values ranging from 0.05 to <1×10-9) were generally stronger when examining haplotypes rather than individual SNPs, and quantitative trait tests most uniformly revealed the detected associations. Consistent risk alleles and haplotypes were apparent across the study, with effects in some cases as large as that of the ε4 allele of APOE. A subsequent mutation screen of exons in all three suspect genes provided no evidence for common causative mutations. These results provide substantial evidence that genetic variation within or extremely close to IDE impacts both disease risk and traits related to the severity of AD. Hum Mutat 22:363–371, 2003. © 2003 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]